Dehydroepiandrosterone (DHEA) is the most abundant adrenal androgen in man, and has been shown to enhance IL-2 production by stimulated human T cells. In patients with systemic lupus erythematosus (SLE), low serum levels of DHEA (and its inactive sulfate ester) as well as defective IL-2 production by T cells have been described regardless of disease activity. Furthermore, administration of DHEA to mice with lupus-like disease in two different models (NZBxNZW and MRL/lpr) was found to improve survival and disease parameters. DHEA has been administered previously to patients with mild to moderate SLE in a double blinded, placebo controlled, randomized clinical trial. The patients who received DHEA experienced greater improvement in all outcome parameters, and were able to reduce glucocorticoid dosages more, than the placebo-treated controls. The drug was generally well tolerated and without serious side effects. A separate study in healthy volunteers suggested modest benefits of DHEA therapy with respect to bone metabolism. To date, no studies have been done of DHEA therapy for severe lupus, but on the basis of these observations benefits might be expected with respect to lupus outcomes, a glucocorticoid sparing effect, and/or amelioration of glucocorticoid- induced osteopenia. In this proposal, DHEA, 200 mg/day orally, will be given to patients with severe SLE in a double-blinded, randomized, placebo controlled, 12 month cross-over trial. Severe disease is defined as any CNS, renal, myocardial, hematologic or visceral manifestations which require the initiation of high dose glucocorticoids (greater than or equal to prednisone 1 mg/kg/day). Outcome measures for this study will be: global outcomes including SLE-DAI score, organ specific outcomes, medication profile (in particular glucocorticoid dose reduction), and bone density. Additionally, the effects of DHEA upon androgen and estrogen levels will be assessed.